Immune response from start to finish: Part 1
[I’ve been hooked on the immune system since I was a kid and my dad showed me electron micrographs of macrophages eating bacteria in Scientific American. Now that I’m in graduate school studying immunology, and macrophages in particular, my dad asked if I could give a play-by-play of an immune response. Here you go Dad:]
Part 1: Invasion and detection, the innate immune system
Most immunology classes I’ve taken have begun with a simple, but profound truth: the best immune response is one that prevents pathogens from ever gaining entry (pathogen = disease-causing organism). Hence, we are covered in barriers. Skin is the most obvious example of a barrier – it’s water-tight, protected by layers of dead cells and covered in things called anti-microbial peptides which are basically tiny protein antibiotics.But other bits of our body can’t be sealed off so completely – the mucosal tissues lining our oral, nasal, genital and gastrointestinal tracts all have to be permeable to carry out their functions – our lungs for instance, which are exposed to the microbial world every time we breathe, would be useless if they were as impenetrable as skin! But that doesn’t mean these tissues are defenseless – they are composed of specialized epithelial cells, which form “tight-junctions,” and secrete mucous and anti-microbial peptides in an effort to be inhospitable.
But these barriers are far from perfect. Evolution has forced compromise – skin is elastic to allow for ease of movement, but that means it’s susceptible to getting cut; the gut epithelium is permeable to nutrients, but also to microbes. In addition, pathogens are masters at subverting even our best defenses (in fact, this is sort of a theme in immunology – we know something is important if we find a pathogen that has learned to get around it). So, once a bug gets past past the initial barriers, what’s next? The immune system needs to know that something is wrong, and that’s where pattern recognition comes in.
I’ve described pattern recognition before, because it’s what I study, but I’ll mention a few things briefly here. Every cell in the body has specialized receptors to detect invading pathogens. These receptors are called pattern-recognition receptors (PRRs) because they recognize parts of pathogens called “PAMPs” – pathogen-associated molecular patterns. All organisms are made of the same basic building blocks (proteins, nucleic acid, lipids and carbohydrates), but bacteria and viruses have some features that are unique, and can therefore be recognized as foreign. Double-stranded RNA, for instance, is never present in the absence of a viral infection. Lipopolysaccharide (LPS) is a sugar that is found in bacterial cell walls, but not in mammals. Not all cells express every PRR, but most cells can at least recognize internally if they get infected.
There are other specialized cells, like macrophages, that are professional pathogen seekers. Macrophages express pattern recognition receptors on their cell-surface called Toll-like receptors (TLRs) that can recognize external bacteria and viruses. The macrophages can then eat the intruders as well as release signals called cytokines that cause inflammation and alert nearby cells of the danger. Inflammation also triggers the influx of neutrophils from the bloodstream – these cells are like kamikazes, eating and destroying everything in their path. Another cell type, natural killer (NK) cells, can recognize signs of infection and stress and force those cells to commit suicide.
These events are enough to clear the vast majority of potential infections, and you would never notice any symptoms. These responses are called the innate immune system, because it’s more or less present in the same form at birth. And the response very general, most viruses and most bacteria will be dealt with in essentially the same way. But real pathogens are sneaky, and they know how to get around these defenses. In Part 2, I’ll talk about the adaptive immune system and the generation of highly specific, coordinated responses to clear prolonged infections.
Immune response from start to finish, the series
Part 1: Invasion and detection: Innate immunity (current)
Part 2: T-cells, B-cells and adaptive immunity
Part 3: Immune Memory
We Beasties 
I have been under the impression that inflammation was our enemy, but after reading this piece, do I understand that inflammation is part of our immune system’s defense weaponry? I am very interested in this subject. Also, is there a place in your immune system explanation where we will learn something about anti-oxidants?
Thanks for reading Aunt Linda! It’s a fine line. Inflammation is the body’s normal response to an infection, causing activation of innate immune cells, recruitment of other cells (like neutrophils) from the blood, and the eventual activation of T-cells and B-cells (which I’ll get to in the next part). Inflammation is great, until it isn’t. Inflammation does cause some tissue damage, but normally this helps clear the infection, and then the inflammation resolves, and the damage is repaired.
The real is problem when you have inflammation in response to harmless things in the environment (that’s what causes allergies), or in response to your own tissues (that’s what causes autoimmune diseases like multiple sclerosis and rheumatoid arthritis). In those cases, the inflammation starts, but can’t resolve because the stimulus sticks around, and the immune system just keeps escalating.
As far as antioxidants go, they don’t figure into the immune system directly. From my understanding though, it’s possible that antioxidants in food can provide some marginal benefit, but most of the supplements and stuff you might buy in the store are more or less useless.
My reading, and Kev will help me out here , is that the NALP3 inflammasome is concerned with oxidative processes gone bad i.e. failure of properly maintained mitochondria. There is no support from the epidemiologic literature that the consumption of known anti oxidants does anything.
To my knowledge, it’s not fully understood what, exactly, the NALP3 inflammasome responds too. Oxidative stress can activate the inflammasome, but so can high levels of extracellular ATP, or disruption of endosomal membranes (like when macrophages try to eat uric acid or cholesterol crystals), and a number of other stimuli. One common theme seems to be the presence of cellular components in places where they are not supposed to be (like mitochondrial matrix in the cytosol), but I don’t think it’s well understood how NALP3 is sensing all those different things.
Kevin,
I enjoyed reading this well written piece. When you said that the neutrophils destroy and eat everything in their path, I was wondering what process tagged the cells as bad as I’m presuming the neutrophils only destroy “bad, marked” cells? Also do these neutrophils self -destruct/die when there are no more bad guys to eat? Do the NK cells also get triggered by the cytokines or are they always running around the body? A more general question I have is how do these various types of cells get transported? Is it always through the blood or are there large numbers of some cells that are distant enough from the bloodstream that other inter cellular travel mechanism comes into play? It is very interesting to me the different strategies in play to get rid of the bad guys. Some good guys eat up the bad guys while others just tap the bad guys on the shoulder and say, commit suicide, and they are obeyed.
There’s a few things that tag cells for destruction. One of the most obvious things is a change in the composition of the cell membrane – the membrane is 2-sided, and cells that are actively dying actually flip their membrane inside out, and neutrophils (and other phagocytes like macrophages) can have receptors that recognize that. Stressed out cells or infected cells can also get coated with antibodies or compliment, and phagocytes have receptors for those too. Neutrophils self-destruct after they’ve worn themselves out or when there are no more pathogens (and their remains are cleaned up by tissue-resident macrophages). They generally have a pretty short life – you really don’t want neutrophils running around when there’s nothing for them to kill, they are pretty destructive.
Thanks for this excellent intro to the immunological system. Can you recommend to me any food to strengthen my innate immunological system? I have developed allergie to dust acari (mites), and are pretty delicate when dealing with the respiratory system. I ingest cod fish oil, hearing all the benefits it gives to my respiratory system. What´s your opinion on that?
I would be very wary of any food supplement that purports to improve immune system function. Supplements are not regulated by the FDA, and do not need to undergo any testing for safety or efficacy. We are just starting to see science tackle some supplements, and the majority don’t actually seem to do anything.
Also, you don’t want to strengthen your immune system if you have allergies – allergies are do to an over-active immune response (most of the drugs used to treat allergies and asthma actually suppress the immune system). I would talk to a doctor about your condition, and don’t get sucked into relying on snake-oil (or fish-oil) remedies.